Extracellular Matrix Structures

ABSTRACT

A sheet structure comprising two joined extracellular matrix (ECM) tissue or sheet layers and a physiological sensor disposed therebetween; the ECM tissue being derived from a mammalian tissue source that includes small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), urinary basement membrane (UBM), liver basement membrane (LBM), amniotic membrane, mesothelial tissue, placental tissue and cardiac tissue.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 15/652,566, filed on Jul. 18, 2017, which is a continuation of U.S. application Ser. No. 14/571,639, filed on Dec. 16, 2014, now U.S. Pat. No. 9,744,264, which is a division of U.S. application Ser. No. 13/896,424, filed on May 17, 2013, now U.S. Pat. No. 9,283,302, which is a continuation-in-part of U.S. application Ser. No. 13/573,566, filed on Sep. 24, 2012, now U.S. Pat. No. 9,066,993, which is a continuation-in-part of U.S. application Ser. No. 13/328,287, filed on Dec. 16, 2011, now U.S. Pat. No. 9,532,943.

FIELD OF THE INVENTION

The present invention relates to methods and apparatus for treating damaged or diseased biological structures. More particularly, the present invention relates to tissue prostheses for treating and/or reconstructing damaged or diseased cardiovascular structures.

BACKGROUND OF THE INVENTION

As is well known in the art, various prostheses are often employed to treat and reconstruct damaged or diseased biological structures and associated tissue, such as cardiovascular vessels and heart tissue. However, despite the growing sophistication of medical technology, the use of prostheses to treat or replace damaged biological tissue remains a frequent and serious problem in health care. The problem is often associated with the materials employed to construct the prostheses.

As is also well known in the art, the optimal prosthesis material should be chemically inert, non-carcinogenic, capable of resisting mechanical stress, capable of being fabricated in the form required and sterilizable. Further, the material should be resistant to physical modification by tissue fluids, and not excite an inflammatory reaction, induce a state of allergy or hypersensitivity, or, in some cases, promote visceral adhesions.

Various materials and/or structures have thus been employed to construct prostheses that satisfy the aforementioned optimal characteristics. Such materials and structures include tantalum gauze, stainless mesh, Dacron®, Orlon®, Fortisan®, nylon, knitted polypropylene (e.g., Marlex®), microporous expanded-polytetrafluoroethylene (e.g., Gore-Tex®), Dacron reinforced silicone rubber (e.g., Silastic®), polyglactin 910 (e.g., Vicryl®), polyester (e.g., Mersilenene®), polyglycolic acid (e.g., Dexon®), processed sheep dermal collagen, crosslinked bovine pericardium (e.g., Peri-Guard®), and preserved human dura (e.g., Lyodura®).

As discussed in detail below, although some of the noted prosthesis materials satisfy some of the aforementioned optimal characteristics, few, if any, satisfy all of the optimal characteristics.

Metallic mesh structures, e.g., stainless steel meshes, are generally inert and resistant to infection. Metallic mesh structures are, however, prone to fragmentation, which can, and in many instances will, occur after the first year of administration.

Synthetic mesh structures are easily molded and, except for nylon, retain their tensile strength in or on the body. Synthetic mesh structures are, however, typically non-resorbable and susceptibility to infection.

A major problem associated with Marlex®, i.e. polypropylene, mesh structures is that with scar contracture, polypropylene mesh structures become distorted and separate from surrounding normal tissue.

A major problem associated with Gore-Tex®, i.e. polytetrafluoroethylene, mesh structures is that in a contaminated wound it does not allow for any macromolecular drainage, which limits treatment of infections.

Thus, readily available, versatile prostheses that are not prone to calcification, thrombosis and intimal hyperplasia would fill a substantial and growing clinical need.

It is therefore an object of the present invention to provide prostheses that substantially reduce or eliminate (i) the risk of thrombosis, (ii) intimal hyperplasia after intervention in a vessel, (iii) the harsh biological responses associated with conventional polymeric and metal prostheses, and (iv) the formation of biofilm, inflammation and infection, when delivered to damaged tissue.

It is another object of the present invention to provide extracellular matrix (ECM) based tissue prostheses that substantially reduce or eliminate (i) the risk of thrombosis, (ii) intimal hyperplasia after intervention in a vessel, (iii) the harsh biological responses associated with conventional polymeric and metal prostheses, and (iv) the formation of biofilm, inflammation and infection, when delivered to damaged tissue; particularly, damaged cardiovascular tissue.

It is another object of the present invention to provide tissue prostheses that modulate inflammation and induce host tissue proliferation, remodeling and regeneration of new tissue and tissue structures with site-specific structural and functional properties, when delivered to damaged cardiovascular tissue.

It is another object of the present invention to provide tissue prostheses that are capable of administering a pharmacological agent to host tissue and, thereby produce a desired biological and/or therapeutic effect.

SUMMARY OF THE INVENTION

The present invention is directed to tissue prostheses for treating and/or reconstructing damaged or diseased biological structures.

In some embodiments of the invention, the tissue prostheses comprise a sheet structure.

In a preferred embodiment, the sheet structure comprises at least one sheet or layer.

In some embodiments, the sheet structures are configured to encase a medical device.

In a preferred embodiment, the tissue prostheses comprise an ECM composition comprising ECM derived from a mammalian tissue source.

In a preferred embodiment, the ECM comprises acellular ECM.

Preferably, the mammalian tissue source is selected from the group comprising small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), central nervous system tissue, epithelium of mesodermal origin, i.e. mesothelial tissue, gastrointestinal tissue, i.e. large and small intestines, placental tissue, cardiac tissue, e.g., pericardium and/or myocardium, kidney tissue, pancreas tissue, lung tissue, and combinations thereof.

In some embodiments of the invention, the ECM composition includes at least one additional biologically active agent or composition, i.e. an agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

In some embodiments of the invention, the biologically active agent comprises a growth factor.

In some embodiments of the invention, the biologically active agent comprises a cell.

In some embodiments, the ECM composition includes at least one pharmacological agent or composition (or drug), i.e. an agent or composition that is capable of producing a desired biological effect in vivo, e.g., stimulation or suppression of apoptosis, stimulation or suppression of an immune response, etc.

In some embodiments of the invention, the pharmacological agent comprises an anti-inflammatory agent or composition.

According to the invention, upon delivery of a tissue prostheses of the invention to damaged tissue; particularly, damaged cardiovascular tissue, modulated healing of the damaged tissue is effectuated, i.e. inflammation modulation and induced host tissue proliferation, remodeling and regeneration of new tissue and tissue structures with site-specific structural and functional properties are effectuated.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the following and more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, and in which like referenced characters generally refer to the same parts or elements throughout the views, and in which:

FIG. 1 is a perspective view of a sheet structure of the invention in a folded configuration to encase a medical device, in accordance with the invention;

FIG. 2 is a front, partial sectional plan view of the sheet structure shown in FIG. 1, illustrating the encasement of a medical device, in accordance with the invention; and

FIG. 3 is a front, partial sectional plan view of another embodiment of a sheet structure, in accordance with the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified apparatus, systems, structures or methods as such may, of course, vary. Thus, although a number of apparatus, systems and methods similar or equivalent to those described herein can be used in the practice of the present invention, the preferred apparatus, systems, structures and methods are described herein.

It is understood that the tet minology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

Further, all publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

As used in this specification and the appended claims, the singular forms “a, and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “an active” includes two or more such actives and the like.

Further, ranges can be expressed herein as from “about” or “approximately” one particular value, and/or to “about” or “approximately” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about” or “approximately”, it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” or “approximately” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “approximately 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed then “less than or equal to 10” as well as “greater than or equal to 10” is also disclosed.

Definitions

The term “medical device”, as used herein, means and includes any device configured for insertion or implantation in the body of a warm blooded mammal, including humans and primates; avians; domestic household or farm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like. The term “medical device” thus includes, without limitation, a pacemaker, defibrillator, synthetic heart valve, ventricular assist device, artificial heart, physiological sensor, catheter, and associated components thereof, including electrical leads and lines associated therewith.

The terms “extracellular matrix”, “ECM” and “ECM material” are used interchangeably herein, and mean and include a collagen-rich substance that is found in between cells in mammalian tissue, and any material processed therefrom, e.g., decellularized ECM. According to the invention, the ECM can be derived from a variety of mammalian tissue sources, including, without limitation, small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), central nervous system tissue, epithelium of mesodermal origin, i.e. mesothelial tissue, dermal tissue, gastrointestinal tissue, i.e. large and small intestine tissue, placental tissue, omentum tissue, cardiac tissue, e.g., pericardium and/or myocardium tissue, kidney tissue, pancreas tissue, lung tissue, and combinations thereof.

The ECM can also comprise collagen from mammalian sources.

The terms “urinary bladder submucosa (UBS)”, “small intestine submucosa (SIS)” and “stomach submucosa (SS)” also mean and include any UBS and/or SIS and/or SS tissue that includes the tunica mucosa (which includes the transitional epithelial layer and the tunica propria), submucosal layer, one or more layers of muscularis, and adventitia (a loose connective tissue layer) associated therewith.

The ECM can also be derived from basement membrane of mammalian tissue/organs, including, without limitation, urinary basement membrane (UBM), liver basement membrane (LBM), and amnion, chorion, allograft pericardium, allograft acellular dermis, amniotic membrane, Wharton's jelly, and combinations thereof.

Additional sources of mammalian basement membrane include, without limitation, spleen, lymph nodes, salivary glands, prostate, pancreas and other secreting glands.

The ECM can also be derived from other sources, including, without limitation, collagen from plant sources and synthesized extracellular matrices, i.e. cell cultures.

The term “angiogenesis”, as used herein, means a physiologic process involving the growth of new blood vessels from pre-existing blood vessels.

The term “neovascularization”, as used herein, means and includes the formation of functional vascular networks that can be perfused by blood or blood components. Neovascularization includes angiogenesis, budding angiogenesis, intussuceptive angiogenesis, sprouting angiogenesis, therapeutic angiogenesis and vasculogenesis.

The terms “biologically active agent” and “biologically active composition” are used interchangeably herein, and mean and include agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

The terms “biologically active agent” and “biologically active composition” thus mean and include, without limitation, the following growth factors: epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), transforming growth factor beta (TGF-beta), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), nerve growth factor (NGF), platelet derived growth factor (PDGF), tumor necrosis factor alpha (TNA-alpha), and placental growth factor (PLGF).

The terms “biologically active agent” and “biologically active composition” also mean and include, without limitation, the cells set forth in Co-pending U.S. application Ser. No. 15/652,566, including human embryonic stem cells, fetal cardiomyocytes, myofibroblasts, mesenchymal stern cells, parenchymal cells, epithelial cells, endothelial cells, mesothelial cells, fibroblasts, osteoblasts and chondrocytes.

The terms “biologically active agent” and “biologically active composition” also mean and include, without limitation, the following biologically active agents (referred to interchangeably herein as a “protein”, “peptide” and “polypeptide”): collagen (types I-V), proteoglycans, glycosaminoglycans (GAGs), glycoproteins, growth factors, cytokines, cell-surface associated proteins, cell adhesion molecules (CAM), angiogenic growth factors, endothelial ligands, matrikines, cadherins, immuoglobins, fibril collagens, non-fibrallar collagens, basement membrane collagens, multiplexins, small-leucine rich proteoglycans, decorins, biglycans, fibromodulins, keratocans, lumicans, epiphycans, heparin sulfate proteoglycans, perlecans, agrins, testicans, syndecans, glypicans, serglycins, selectins, lecticans, aggrecans, versicans, neurocans, brevicans, cytoplasmic domain-44 (CD-44), macrophage stimulating factors, amyloid precursor proteins, heparins, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate A, heparin sulfates, hyaluronic acids, fibronectins, tenascins, elastins, fibrillins, laminins, nidogen/enactins, fibulin I, finulin II, integrins, transmembrane molecules, thrombospondins, ostepontins, and angiotensin converting enzymes (ACE).

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” are used interchangeably herein, and mean and include an agent, drug, compound, composition of matter or mixture thereof, including its formulation, which provides some therapeutic, often beneficial, effect. This includes any physiologically or pharmacologically active substance that produces a localized or systemic effect or effects in animals, including warm blooded mammals, humans and primates; avians; domestic household or farm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” thus mean and include, without limitation, the pharmacological agents set forth in Co-pending U.S. application Ser. No. 15/652,566, including antibiotics, anti-arrhythmic agents, anti-viral agents, analgesics, anti-inflammatory agent, anti-neoplastics, anti-spasmodics, modulators of cell-extracellular matrix interactions, proteins, hormones, growth factors, matrix metalloproteinases (MMPS), enzymes and enzyme inhibitors, anticoagulants and/or antithrombotic agents, DNA, RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides, oligonucleotides, polynucleotides, nucleoproteins, compounds modulating cell migration, compounds modulating proliferation and growth of tissue, and vasodilating agents.

The terms “anti-inflammatory” and “anti-inflammatory agent” are also used interchangeably herein, and mean and include a “pharmacological agent” and/or “active agent formulation”, which, when a therapeutically effective amount is administered to a subject, prevents or treats bodily tissue inflammation i.e. the protective tissue response to injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissues.

Anti-inflammatory agents thus include, without limitation, the anti-inflammatory agents also set forth in Co-pending U.S. application Ser. No. 15/652,566.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” also mean and include the following Class I-Class V anti-arrhythmic agents: (Class Ia) quinidine, procainamide and disopyramide; (Class Ib) lidocaine, phenytoin and mexiletine; (Class Ic) flecainide, propafenone and moricizine; (Class II) propranolol, esmolol, timolol, metoprolol and atenolol; (Class III) amiodarone, sotalol, ibutilide and dofetilide; (Class IV) verapamil and diltiazem) and (Class V) adenosine and digoxin.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” further mean and include, without limitation, the following antibiotics: aminoglycosides, cephalosporins, chloramphenicol, clindamycin, erythromycins, fluoroquinolones, macrolides, azolides, metronidazole, penicillins, tetracyclines, trimethoprim-sulfamethoxazole and vancomycin.

The term “pharmacological composition”, as used herein, means and includes a composition comprising a “pharmacological agent” and/or a “biologically active agent” and/or any additional agent or component identified herein.

The term “therapeutically effective”, as used herein, means that the amount of the “pharmacological composition” and/or “pharmacological agent” and/or “biologically active agent” administered is of sufficient quantity to ameliorate one or more causes, symptoms, or sequelae of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination, of the cause, symptom, or sequelae of a disease or disorder.

The terms “prevent” and “preventing” are used interchangeably herein, and mean and include reducing the frequency or severity of a disease or condition. The term does not require an absolute preclusion of the disease or condition. Rather, this term includes decreasing the chance for disease occurrence.

The terms “treat” and “treatment” are used interchangeably herein, and mean and include medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. The terms include “active treatment”, i.e. treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and “causal treatment”, i.e. treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.

The terms “treat” and “treatment” further include “palliative treatment”, i.e. treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder, “preventative treatment”, i.e. treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder, and “supportive treatment”, i.e. treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

The terms “patient” and “subject” are used interchangeably herein, and mean and include warm blooded mammals, humans and primates; avians; domestic household or farm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like.

The term “comprise” and variations of the term, such as “comprising” and “comprises,” means “including, but not limited to” and is not intended to exclude, for example, other additives, components, integers or steps.

The following disclosure is provided to further explain in an enabling fashion the best modes of performing one or more embodiments of the present invention. The disclosure is further offered to enhance an understanding and appreciation for the inventive principles and advantages thereof, rather than to limit in any manner the invention. The invention is defined solely by the appended claims, including any amendments made during the pendency of this application, and all equivalents of those claims as issued.

As discussed above, in one embodiment, the present invention is directed to tissue prostheses for treating and/or reconstructing damaged or diseased biological structures; particularly, cardiovascular structures.

In a preferred embodiment of the invention, the tissue prostheses comprise a sheet structure.

In a preferred embodiment, the sheet structure comprises at least one sheet or layer.

In some embodiments, the sheet structure comprises at least two sheets or sheet layers.

In a preferred embodiment, the sheet structures of the invention are configured to encase a medical device.

In some embodiments, the medical device comprises a physiological sensor.

In a preferred embodiment, the tissue prostheses comprise an ECM composition comprising ECM derived from a mammalian tissue source.

According to the invention, upon delivery of the tissue prostheses of the invention to damaged tissue of a biological structure; particularly, damaged cardiovascular tissue of a cardiovascular structure, modulated healing of the damaged tissue is effectuated.

The phrase “modulated healing”, as used herein, and variants of this language generally refer to the modulation (e.g., alteration, delay, retardation, reduction, etc.) of a process involving different cascades or sequences of naturally occurring tissue repair in response to localized tissue damage or injury, substantially reducing their inflammatory effect. Modulated healing, as used herein, includes many different biologic processes, including epithelial growth, fibrin deposition, platelet activation and attachment, inhibition, proliferation and/or differentiation, connective fibrous tissue production and function, angiogenesis, and several stages of acute and/or chronic inflammation, and their interplay with each other.

For example, in some embodiments, the ECM compositions and, hence, tissue prostheses of the invention are specifically formulated (or designed) to alter, delay, retard, reduce, and/or detain one or more of the phases associated with healing of damaged tissue, including, but not limited to, the inflammatory phase (e.g., platelet or fibrin deposition), and the proliferative phase.

In some embodiments, “modulated healing” refers to the ability of an ECM composition and, hence, prosthesis to alter a substantial inflammatory phase (e.g., platelet or fibrin deposition) at the beginning of the tissue healing process. As used herein, the phrase “alter a substantial inflammatory phase” refers to the ability of an ECM composition to substantially reduce the inflammatory response at an injury site.

In such an instance, a minor amount of inflammation may ensue in response to tissue injury, but this level of inflammation response, e.g., platelet and/or fibrin deposition, is substantially reduced when compared to inflammation that takes place in the absence of an ECM composition and, hence, tissue prosthesis of the invention.

In some embodiments of the invention, “modulated healing” refers to the ability of an ECM composition and, hence, tissue prosthesis of the invention to induce host tissue proliferation, bioremodeling, including neovascularization, e.g., vasculogenesis, angiogenesis, and intussusception, and regeneration of tissue structures with site-specific structural and functional properties.

Accordingly, the ECM compositions and, hence, tissue prostheses discussed herein provide an excellent bioabsorbable cellular interface suitable for use with a medical device or surgical instrument.

As indicated above, the tissue prostheses comprise sheet structures that can be configured to encase a medical device.

According to the invention, the encased medical device and associated components can comprise, without limitation, a pacemaker, defibrillator, synthetic heart valve, ventricular assist device, artificial heart, physiological sensor, catheter, and the electrical leads and lines associated therewith.

As indicated above, in a preferred embodiment, the tissue prostheses of the invention comprise an ECM composition comprising ECM derived from a mammalian tissue source.

According to the invention, the ECM can be derived from various mammalian tissue sources and methods for preparing same, such as disclosed in U.S. Pat. Nos. 7,550,004, 7,244,444, 6,379,710, 6,358,284, 6,206,931, 5,733,337 and 4,902,508 and U.S. application Ser. No. 12/707,427; which are incorporated by reference herein in their entirety.

In a preferred embodiment, the mammalian tissue sources include, without limitation, small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), central nervous system tissue, epithelium of mesodermal origin, i.e. mesothelial tissue, dermal tissue, gastrointestinal tissue, i.e. large and small intestine tissue, placental tissue, omentum tissue, cardiac tissue, e.g., pericardium and/or myocardium tissue, kidney tissue, pancreas tissue, lung tissue, and combinations thereof. The ECM can also comprise collagen from mammalian sources.

The ECM can also be derived from the same or different mammalian tissue sources, as disclosed in Co-Pending application Ser. Nos. 13/033,053 and 13/033,102, now U.S. Pat. No. 8,758,448; which are incorporated by reference herein.

In a preferred embodiment, the ECM comprises acellular ECM, more preferably sterilized, acellular ECM.

According to the invention, the ECM can be sterilized via applicant's proprietary sterilization (i.e. Novasterillis®) process, as disclosed in Co-Pending U.S. application Ser. No. 13/480,205; which is expressly incorporated herein in its entirety.

As stated above, in some embodiments of the invention, the ECM compositions and, hence, tissue prostheses formed therefrom include at least one additional biologically active agent or composition, i.e. an agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

Suitable biologically active agents include any of the aforementioned biologically active agents, including, without limitation, the aforementioned cells, proteins and growth factors.

In some embodiments, the ECM compositions and, hence, tissue prostheses formed therefrom include at least one pharmacological agent or composition (or drug), i.e. an agent or composition that is capable of producing a desired biological effect in vivo, e.g., stimulation or suppression of apoptosis, stimulation or suppression of an immune response, etc.

Suitable pharmacological agents and compositions include any of the aforementioned agents, including, without limitation, antibiotics, anti-viral agents, analgesics, steroidal anti-inflammatories, non-steroidal anti-inflammatories, anti-neoplastics, anti-spasmodics, modulators of cell-extracellular matrix interactions, proteins, hormones, enzymes and enzyme inhibitors, anticoagulants and/or antithrombotic agents, DNA, RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides, oligonucleotides, polynucleotides, nucleoproteins, compounds modulating cell migration, compounds modulating proliferation and growth of tissue, and vasodilating agents.

In some embodiments of the invention, the pharmacological agent comprises an anti-inflammatory agent.

In some embodiments of the invention, the pharmacological agent comprises a statin, i.e. a HMG-CoA reductase inhibitor. According to the invention, suitable statins include, without limitation, atorvastatin (Lipitor®), cerivastatin, fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®), mevastatin, pitavastatin (Livalo ®, Pitava®), pravastatin (Pravachol®, Selektine®, Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®, Lipex®). Several actives comprising a combination of a statin and another agent, such as ezetimbe/simvastatin (Vytorin®), are also suitable.

Applicant has found that the noted statins exhibit numerous beneficial properties that provide several beneficial biochemical actions or activities. The properties and beneficial actions are set forth in Applicant's Co-Pending application Ser. Nos. 13/573,569, now U.S. Pat. No. 9,072,816, filed on Sep. 24, 2012 and 13/782,024, now U.S. Pat. No. 9,044,319, filed on Mar. 1, 2013; which are incorporated by reference herein in their entirety.

According to the invention, the amount of a pharmacological agent added to an ECM composition of the invention will, of course, vary from agent to agent. For example, in one embodiment, wherein the pharmacological agent comprises dicloflenac (Voltaren®), the amount of dicloflenac included in the ECM composition is preferably in the range of 10 μg-75 mg.

According to the invention, the biologically active and pharmacological agents referenced above can comprise any form. In some embodiments of the invention, the biologically active and pharmacological agents, e.g. simvastatin, comprise microcapsules that provide delayed delivery of the agent contained therein.

Referring now to FIGS. 1 and 2, there is shown one embodiment of a sheet structure 14 of the invention in a folded “pouch” configuration 10 having a cavity therein 13 that is adapted to encase a bi-ventricular (Bi-V) pacemaker 20 (shown in phantom lines in FIG. 1).

As set forth in priority U.S. application Ser. No. 13/573,566, which is incorporated by reference herein in its entirety, in a preferred embodiment, the sheet structure 14 comprises at least one layer or sheet of ECM material comprising an ECM composition of the invention.

As indicated above, in a preferred embodiment, the sheet structure 14 comprises an ECM composition comprising acellular ECM.

As also indicated above, in some embodiments of the invention, the ECM composition and, hence, ECM sheet structure 14 formed therefrom includes at least one of the aforementioned biologically active agents, including, without limitation, the aforementioned cells, proteins and growth factors.

In some embodiments, the ECM composition and, hence, ECM sheet structure 14 formed therefrom includes at least one of the aforementioned agents, including, without limitation, antibiotics, anti-viral agents, analgesics, and steroidal and non-steroidal anti-inflammatories.

According to the invention, the biologically active and pharmacological agents can be incorporated into the ECM composition (and/or material) and/or deposited on the outer surface 12 of the sheet structure 14.

As also set forth in priority U.S. application Ser. No. 13/573,566, according to the invention, the sheet structure 14 can also include more than one layer of ECM material, e.g. two (2), three (3) ECM layers, etc. The layers can also comprise the same material, i.e. ECM composition, or different materials or compositions.

Referring now to FIG. 3 (originally FIG. 4 of Priority U.S. application Ser. No. 13/573,566), there is shown another embodiment of sheet structure 25.

As illustrated in FIG. 3, the sheet structure 25 comprises two (2) sheets or sheet layers 15 a, 15 b comprising an ECM composition of the invention (i.e. a composition comprising decellularized ECM from a mammalian tissue source).

As also illustrated in FIG. 3, the ECM sheet layers 15 a, 15 b are sized, configured and positioned to receive and contain a medical device 30 therebetween.

In a preferred embodiment, the medical device 30 comprises a physiological sensor.

As further illustrated in FIG. 3, in some embodiments, the ECM sheet layers 15 a, 15 b are joined or laminated on at least ends 19 a, 19 b.

According to the invention, the ECM sheet layers 15 a, 15 b can be joined or laminated by various conventional means, such as stitching, including ECM stitches, staples and adhesives. The ECM sheet layers 15 a, 15 b can also be laminated via microneedles and/or microneedle structures, such as disclosed in U.S. Pat. No. 8,778,012.

As will readily be appreciated by one having ordinary skill in the art, the present invention provides numerous advantages compared to prior art prostheses. Among the advantages are the following:

-   -   The provision of tissue prostheses that substantially reduce or         eliminate (i) the risk of thrombosis, (ii) intimal hyperplasia         after intervention in a vessel, (iii) the harsh biological         responses associated with conventional polymeric and metal         prostheses, and (iv) the formation of biofilm, when delivered to         damaged tissue; particularly, damaged cardiovascular tissue.     -   The provision of tissue prostheses that modulate inflammation         and induce host tissue proliferation, remodeling and         regeneration of new tissue and tissue structures with         site-specific structural and ftmctional properties, when         delivered to damaged tissue; particularly, damaged         cardiovascular tissue.     -   The provision of tissue prostheses that are capable of         administering a pharmacological agent to host tissue and,         thereby produce a desired biological and/or therapeutic effect.     -   The provision of ECM based sheet structures that can be         configured to encase a medical device therein, and effectively         improve biological functions and/or promote modulated healing of         adjacent tissue and the growth of new tissue when implanted in         the body.

Without departing from the spirit and scope of this invention, one of ordinary skill can make various changes and modifications to the invention to adapt it to various usages and conditions. As such, these changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of any subsequently proffered claims. 

What is claimed is:
 1. A tissue prosthesis, comprising: a remodelable sheet structure comprising a first sheet layer, a second sheet layer, and a physiological sensor, said physiological sensor being disposed between said first and second sheet layers, said first sheet layer comprising a first top surface and a first bottom surface, said second sheet layer comprising a second top surface and a second bottom surface, said first sheet layer comprising a first extracellular matrix (ECM) composition comprising first decellularized ECM derived from a first mammalian tissue source, said second sheet layer comprising a second extracellular matrix (ECM) composition comprising second decellularized ECM derived from a second mammalian tissue source, said first and second sheet layers, when delivered to damaged tissue, being adapted to reduce an inflammatory phase of said damaged tissue and induce host tissue proliferation, bioremodeling and, thereby, neovascularization of said damaged tissue, and regeneration of tissue structures, said first and second sheet layers being joined, wherein said first sheet layer first bottom surface is in communication with said second sheet layer second top surface, and said physiological sensor is encased by said first and second sheet layers.
 2. The tissue prosthesis of claim 1, wherein said first mammalian tissue source comprises mammalian tissue selected from the group consisting of small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), urinary basement membrane (UBM), liver basement membrane (LBM), amniotic membrane, mesothelial tissue, placental tissue and cardiac tissue.
 3. The tissue prosthesis of claim 1, wherein said first ECM composition comprises at least a first additional biologically active agent.
 4. The tissue prosthesis of claim 3, wherein said first biologically active agent comprises a growth factor selected from the group consisting of a basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF).
 5. The tissue prosthesis of claim 1, wherein said second mammalian tissue source comprises mammalian tissue selected from the group consisting of small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), urinary basement membrane (UBM), liver basement membrane (LBM), amniotic membrane, mesothelial tissue, placental tissue and cardiac tissue.
 6. The tissue prosthesis of claim 1, wherein said second ECM composition comprises at least a second additional biologically active agent.
 7. The tissue prosthesis of claim 6, wherein said second biologically active agent comprises a growth factor selected from the group consisting of bFGF, TGF-β and VEGF.
 8. The tissue prosthesis of claim 1, wherein said first and second sheet layers are joined via a microneedle structure. 